Beta-hydroxybutyric acid compositions and methods for delivery of ketone bodies

ABSTRACT

Beta-hydroxybutyric acid compositions for oral delivery are substantially free of beta-hydroxybutyrate salts and are effective in rapidly raising blood ketone levels without causing acute acidosis or gastrointestinal (GI) distress when consumed in sufficiently dilute form and/or as a gel or suspension. By excluding beta-hydroxybutyrate salts (e.g., less than 1% by weight) containing alkali or alkaline earth metal ions, beta-hydroxybutyric acid solutions, gels, or suspensions can deliver exogenous ketone bodies without significantly altering electrolyte balance. Although aqueous beta-hydroxybutyric acid solutions are moderately acidic with a pH of about 3.5 to 4, when diluted with sufficient water, the water acts as a pseudo buffering agent that offsets otherwise harsh acidic effects when consumed orally. Gels and suspensions can also ameliorate acidic effects by partially encapsulating the beta-hydroxybutyric acid. Beta-hydroxybutyric acid can be enriched with the R- or the S-enantiomer, a racemic mixture, pure R-beta-hydroxybutyric acid, or pure S-beta-hydroxybutyric acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation-in-part of U.S. Pat. App. No.17/210,646, filed Mar. 24, 2021, which is a continuation-in-part of U.S.Pat. App. No. 17/157,000, filed Jan. 25, 2021, which is a continuationof U.S. Pat. App. No. 16/381,202, filed Apr. 11, 2019, now issued U.S.Pat. No. 10,925,843, which claims the benefit of U.S. Prov. App. No.62/659,564, filed Apr. 18, 2018.

U.S. Pat. App. No. 17/210,646 is also a continuation-in-part of U.S.Pat. App. No. 17/130,498, filed Dec. 12, 2020, now issued U.S. Pat. No.11,202,769, and is a continuation-in-part of U.S. Pat. App. No.16/996,509, filed Aug. 18, 2020, now issued U.S. Pat. No. 10,973,786,which is a continuation-in-part of U.S. Pat. App. No. 16/720,211, filedDec. 19, 2019, now issued U.S. Pat. No. 11,202,362, and is also acontinuation-in-part of U.S. Pat. App. No. 16/783,844, filed Feb. 6,2020, now issued U.S. Pat. No. 11,103,470, and a continuation-in-part ofU.S. Pat. App. No. 16/783,886, filed Feb. 6, 2020, now issued U.S. Pat.No. 11,185,518, and a continuation-in-part of U.S. Pat. App. No.17/190,062, filed Mar. 2, 2021, now issued U.S. Pat. No. 11,419,836,which is a continuation-in-part of U.S. Pat. App. No. 16/783,956, filedFeb. 6, 2020, now issued U.S. Pat. No. 10,973,792, which claims thebenefit of U.S. Prov. App. No. 62/805,054, filed Feb. 13, 2019, and isalso a continuation-in-part of U.S. Pat. App. No. 16/783,907, filed Feb.6, 2020, now issued U.S. Pat. No. 11,241,401, and a continuation-in-partof U.S. Pat. App. No. 16/551,570, filed Aug. 26, 2019, now issued U.S.Pat. No. 11,129,802, which is a continuation-in-part of U.S. Pat. App.No. 16/272,359, filed Feb. 11, 2019, now issued U.S. Pat. No.10,512,615, which claims the benefit of U.S. Prov. App. No. 62/769,412,filed Nov. 19, 2018, U.S. Prov. App. No. 62/760,430, filed Nov. 13,2018, and U.S. Prov. App. No. 62/723,274, filed Aug. 27, 2018, and isalso a continuation-in-part of U.S. Pat. App. No. 16/551,594, filed Aug.26, 2019, which is a continuation-in-part of U.S. Pat. App. No.16/272,328, filed Feb. 11, 2019, now issued U.S. Pat. No. 10,980,772,which claims the benefit of U.S. Prov. App. No. 62/769,432, filed Nov.19, 2018, U.S. Prov. App. No. 62/760,462, filed Nov. 13, 2018, and U.S.Prov. App. No. 62/723,283, filed Aug. 27, 2018.

U.S. Pat. App. No. 17/210,646 also claims the benefit of U.S. Prov. App.No. 63/070,532, filed Aug. 26, 2020.

The foregoing patents and applications are incorporated by reference intheir entirety.

BACKGROUND 1. Field of The Invention

The invention relates to aqueous drinks, liquid and powder drinkadditives, and liquid and powder food additives containingbeta-hydroxybutyric acid and methods for delivering exogenous ketonebodies to a subject in need thereof.

2. Related Technology

In periods of fasting, extreme exercise, and/or low carbohydrateconsumption, glucose and glycogen stores in the body are rapidly usedand can become quickly depleted. As glucose stores are depleted, thebody metabolically shifts to creation of ketone bodies for energy.Ketone bodies can be used by cells of the body as fuel to satisfy thebody’s energy needs. During prolonged fasting, for example, blood ketonelevels can increase to 2-3 mmol/L or more. It is conventionallyunderstood that when blood ketones rise above 0.5 mmol/L, the heart,brain, and peripheral tissues use ketone bodies (e.g.,beta-hydroxybutyrate and acetoacetate) as the primary fuel source. Thiscondition is referred to as “ketosis”. Between 1.0 mmol/L and 3.0 mmol/Lthe condition is called “nutritional ketosis.”

Upon transitioning into ketosis, i.e., during ketogenic metabolism inthe liver, the body uses dietary and bodily fats as a primary energysource. Consequently, when in ketosis, one can induce loss of body fatby controlling dietary fat intake and maintaining low carbohydrateintake and blood level to sustain ketosis.

While in ketosis, the body is in ketogenesis and is essentially burningfat for its primary fuel. The body cleaves fats into fatty acids andglycerol and transforms fatty acids into acetyl CoA molecules, which aretransformed through ketogenesis into the water-soluble ketone bodiesbeta-hydroxybutyrate (“β-hydroxybutyrate” or “beta-hydroxybutyrate”),acetoacetate, and acetone in the liver. Beta-hydroxybutyrate andacetoacetate are used by the body for energy, while acetone is removedas a by-product of ketogenesis.

The metabolism of ketone bodies is associated with several improvementsto metabolic function, such as anticonvulsant effects, enhancedmetabolism by the brain, neuroprotection, muscle sparing properties,improved cognitive and physical performance, and epigenetic effects(positive or beneficial gene expressions). Science-based improvements inefficiency of cellular metabolism, managed through ketonesupplementation, can have beneficial impacts on physical, cognitivehealth, and psychological health, and a long-term impact on health withrespect to the common avoidable diseases such as obesity, cardiovasculardisease, neurodegenerative diseases, diabetes, and cancer.

Ketone bodies are most often administered as salts or esters. Ketonesalts are generally safe but can introduce excessive quantities ofelectrolytes when consumed in excess. Ketone esters do not contributeelectrolytes but must be hydrolyzed before they are usable as ketonebodies. Downsides of ketone esters is they can have unpleasant taste andintroduce alcohol into the body when hydrolyzed.

Free acid forms of beta-hydroxybutyrate and acetoacetate are used lessfrequently. It has been reported that solutions of racemicbeta-hydroxybutyric acid have been administered intravenously. Dilutesolutions are required when ketone body acids are deliveredintravenously to prevent negative effects of low pH and isotonicdeficiency. For example, a 1 mmol/L beta-hydroxybutyric acid solutioncontains only 0.0104% w/v of ketone bodies. Such solutions are uselessfor oral delivery of ketone bodies because one would have to consumeapproximately 10 liters to obtain 1 gram of ketone bodies.

Some have proposed oral delivery of ketone bodies as partially bufferedacid compositions. For example, US Pub. No. 2018/0057846 (Llosa et al.)discloses solutions containing partially buffered enantiomerically pureor enriched D-beta-hydroxybutyrate compositions with up to at most 99%free acid, at least 1% ketone salt, at least 1% 1,3-butanediol, and atleast 1% ketone ester. Llosa et al. further teach that “[t]he use ofpure, free acid form of β-HB at the upper limit of therapeutic doses hasbeen considered undesirable due to the possibility of acute acidosis orgastrointestinal (GI) distress” and “the β-hydroxy group is unstable inthe presence of low pH” (paragraph [0035]). US Pub. No. US 2018/0021274(Amold et al.) discloses compositions containing beta-hydroxybutyricacid and beta-hydroxybutyrate salt in ratios of up to “~125 parts freeacid per ~7 parts salt” (paragraph [0019]), which equates to a free acidconcentration of up to about 94.7% by weight and a salt concentration ofat least about 5.3% by weight.

SUMMARY

It has been unexpectedly found that aqueous beta-hydroxybutyric acidcompositions for oral delivery that are free or substantially free ofbeta-hydroxybutyrate salts are effective in rapidly raising blood ketonelevels without causing acute acidosis or gastrointestinal (GI) distresswhen consumed in sufficiently dilute form. In the absence of significantquantities of beta-hydroxybutyrate salts containing alkali or alkalineearth metal ions, aqueous beta-hydroxybutyric acid solutions can deliverexogenous ketone bodies without significantly altering electrolytebalance. By providing aqueous beta-hydroxybutyric acid at aconcentration within specific ranges, it is possible to maintainbeta-hydroxybutyric acid stability and prevent self-esterification andprecipitation.

In some embodiments, aqueous beta-hydroxybutyric acid solutions can havea concentration that is sufficiently diluted such that volumes of about4 oz. (about 120 ml) to about 16 oz. (about 475 ml) can deliver aquantity of ketone bodies in a range of about 0.5 gram to about 25grams, without harming the stomach or causing significant acidosis. Forexample, dilute aqueous beta-hydroxybutyric acid solutions can have aconcentration of beta-hydroxybutyric acid in a range of about 0.4% w/vto about 6% w/v. Although aqueous beta-hydroxybutyric acid solutions aremoderately acidic, with a pH of about 3.5 to 4, when diluted withsufficient water, the water itself acts as a pseudo buffering agent thatoffsets the otherwise harsh effects of the acid when consumed orally.

In some embodiments, aqueous beta-hydroxybutyric acid solutions can beprovided as a concentrate for later dilution by the user, such as withwater, juice, drink, energy shot, or other aqueous composition to aconcentration in a range of about 0.4% w/v to about 6% w/v. Concentratedsolutions may comprise beta-hydroxybutyric acid in a range of about 6%w/v to about 60% w/v and then diluted by the user as desired, such asfrom about 2 to about 30 times, with water, juice, drink, or otheraqueous composition, as desired. Preferably, the aqueousbeta-hydroxybutyric acid solutions will not be so concentrated so as toself-polymerize and form significant amounts of precipitates, althoughit should be understood that such polymerized precipitates are harmlesswhen consumed with sufficient water but lack the efficacy of themonomeric form of beta-hydroxybutyric acid.

In some embodiments, concentrated or dilute beta-hydroxybutyric acidsolutions can be manufactured by combining a powder or other solid formof beta-hydroxybutyric acid with water, drink, beverage, sauce, gel, orother liquid or semiliquid drink, energy product, or food product. Whenthe beta-hydroxybutyric acid solution, drink, sauce, or gel is preparedby a user, the powder or other solid form of beta-hydroxybutyric acidcan be flavored and may contain other additives, such as one or more ofstabilizer, vitamin, mineral, stimulant, nootropic, vasodilator,cannabinoid, amino acid, and the like. The powder may be provided inindividual pre-dosed packets, pouches, tablets, or capsules, or it maybe provided in a kit with a measuring device configured to measure out apredetermined dose or fraction thereof. A plurality (e.g., 2 or 3) ofdissolvable tablets representing a single dose can be packaged togetherin a packet, pouch, or other container. In some embodiments, adissolvable tablet may be effervescent and fizz when added to water. Inthe case of an effervescent tablet, it may be desirable to include aquantity of an edible acid (e.g., citric or malic) together with abicarbonate or carbonate salt to provide the desired effervescent actionyet provide less than 1% of total beta-hydroxybutyrate salt(s) upondissolution in water (i.e., if the edible acid has a lower pKa thanbeta-hydroxybutyric acid a salt of the edible acid will formpreferentially over beta-hydroxybutyrate salt).

Beta-hydroxybutyric acid compositions are free or substantially free ofbeta-hydroxybutyrate salts so as to contain less than 1% of one or morebeta-hydroxybutyrate salts by combined weight of beta-hydroxybutyricacid and beta-hydroxybutyrate salt(s). In currently preferredembodiments, beta-hydroxybutyric acid compositions are essentially ortotally free of beta-hydroxybutyrate salts, i.e., contain 0% by weightof beta-hydroxybutyrate salts.

Aqueous beta-hydroxybutyric acid compositions containing less than 1% ofone or more beta-hydroxybutyrate salts by combined weight ofbeta-hydroxybutyric acid and beta-hydroxybutyrate salt(s) inherentlyhave an acidic pH (i.e., pH of less than 7) because beta-hydroxybutyricacid, a weak acid, has a pKa of 4.7. Depending on the concentration ofbeta-hydroxybutyric acid in water and the amount, if any, ofbeta-hydroxybutyrate salt(s) and/or other edible acid(s), the pH ofaqueous beta-hydroxybutyric acid compositions will typically be lessthan 6.5, preferably less than about 6, or less than about 5.5, or lessthan about 5, or less than about 4.5, or less than about 4 (e.g.,between about 3.5 to 4).

In some embodiments, the beta-hydroxybutyric acid compositions maycontain one or more nutritionally or pharmaceutically acceptablecarriers or additives in addition to water. For example,beta-hydroxybutyric acid compositions may optionally include at leastone additive selected from acetoacetic acid, 1,3-butanediol,beta-hydroxybutyrate esters, acetoacetate esters, vitamins, minerals,central nervous system stimulants, nootropics, edible acids, aminoacids, muscle-promoting compounds (e.g., beta-hydroxybeta-methylbutyrate), one or more cannabinoids (e.g.,tetrahydrocannabinol and/or cannabidiol), and the like.

Where it is desired to deliver essentially pure beta-hydroxybutyricacid, the beta-hydroxybutyric acid compositions will preferably containgreater than 99% by weight of beta-hydroxybutyric acid and less than 1%,less than about 0.9%, less than about 0.8%, less than about 0.7%, lessthan about 0.6%, or less than about 0.5%, by combined weight ofbeta-hydroxybutyrate salt(s), 1,3-butanediol, and ketone esters (i.e.,beta-hydroxybutyrate and/or acetoacetate esters) by total combinedweight of the beta-hydroxybutyric acid and any of beta-hydroxybutyratesalt(s), 1,3-butanediol, or ketone ester that may be present, exclusiveof water and other components unrelated to ketone bodies. Stated anotherway, beta-hydroxybutyric acid compositions can have a weight ratio ofbeta-hydroxybutyric acid to combined beta-hydroxybutyrate salt(s),1,3-butanediol, and ketone esters or greater than 99:1, greater thanabout 99.1:0.9, greater than about 99.2:0.8, greater than about99.3:0.7, greater than about 99.4:0.6, or greater than about 99.5:0.5.

In various embodiments, beta-hydroxybutyric acid compositions mayinclude enantiomerically pure R-beta-hydroxybutyric acid,enantiomerically pure S-beta-hydroxybutyric acid, a racemic mixture ofR- and S-beta-hydroxybutyric acid (i.e., a mixture having a 1:1enantiomeric ratio of R-beta-hydroxybutyric acid andS-beta-hydroxybutyric acid), a non-racemic mixture enriched with theR-enantiomer, or a non-racemic mixture enriched with the S-enantiomer.In some embodiments it is advantageous to include at least some amountof S-beta-hydroxybutyric acid in addition to or instead ofR-beta-hydroxybutyric acid.

In a first embodiment, beta-hydroxybutyric acid compositions contain anon-racemic mixture enriched with the R-enantiomer, such as greater than50% and less than 100% by enantiomeric equivalents of exogenousR-beta-hydroxybutyric acid and less than 50% and greater than 0% byenantiomeric equivalents of exogenous S-beta-hydroxybutyric acid.

In a second embodiment, beta-hydroxybutyric acid compositions contain anon-racemic mixture enriched with the S-enantiomer, such as greater than50% and less than 100% by enantiomeric equivalents of exogenousS-beta-hydroxybutyric acid and less than 50% and greater than 0% byenantiomeric equivalents of exogenous R-beta-hydroxybutyric acid.

In a third embodiment, beta-hydroxybutyric acid compositions contain aracemic mixture of R-beta-hydroxybutyric acid and S-beta-hydroxybutyricacid, i.e., that contains 50% by enantiomeric equivalents of exogenousR-beta-hydroxybutyric acid and 50% by enantiomeric equivalents ofexogenous S-beta-hydroxybutyric acid.

In a fourth embodiment, beta-hydroxybutyric acid compositions containenantiomerically pure S-beta-hydroxybutyric acid, i.e., that contains100% by enantiomeric equivalents of exogenous S-beta-hydroxybutyric acidand 0% by enantiomeric equivalents of R-beta-hydroxybutyric acid.

In a fifth embodiment, beta-hydroxybutyric acid compositions containenantiomerically pure R-beta-hydroxybutyric acid, i.e., that contains100% by enantiomeric equivalents of exogenous R-beta-hydroxybutyric acidand 0% by enantiomeric equivalents of S-beta-hydroxybutyric acid.

It is generally understood that only enantiomerically pureR-beta-hydroxybutyric acid and/or R-beta-hydroxybutyrate is producedendogenously and naturally by mammals so as to be a natural product. Atnormal biological pH (i.e., between 7.35 and 7.45), the endogenous formof beta-hydroxybutyric acid only exists as substantially deprotonatedR-beta-hydroxybutyrate anions and not as a powder, solid, concentratedsolution, or even dilute R-beta-hydroxybutyric acid solution within thedisclosed concentrations.

S-beta-hydroxybutyric acid (S-beta-hydroxybutyrate at biological pH),which is not endogenously produced by mammals and is believed by some tobe unnatural and potentially harmful, can provide other beneficialeffects. These include one or more of: increased endogenous productionof R-beta-hydroxybutyrate and acetoacetate; endogenous conversion intoone or both of R-beta-hydroxybutyrate and acetoacetate; endogenousconversion into fatty acids and sterols; prolonged ketosis; metabolismof S-beta-hydroxybutyrate independent of its conversion toR-beta-hydroxybutyrate and/or acetoacetate; improved fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling to modulate metabolism of R-beta-hydroxybutyrate andglucose; antioxidant activity; and production of acetyl-CoA.

Beta-hydroxybutyric acid compositions that are enriched with, or containenantiomerically pure, S-beta-hydroxybutyric acid may be administered inhigher doses than compositions enriched with, or that containenantiomerically pure, R-beta-hydroxybutyric acid to obtain the samerapid supply of R-beta-hydroxybutyrate in the body. In such cases, itmay be desirable to include incrementally higher, but still small,amounts of beta-hydroxybutyrate salts, such as less than 4%, 3%, or 2%of such salts by combined weight of beta-hydroxybutyric acid andbeta-hydroxybutyrate salt(s), in order to further offset the acidity ofbeta-hydroxybutyric acid.

Beta-hydroxybutyric acid compositions disclosed herein may function toinduce and/or sustain ketosis in a subject to which the composition isadministered without significantly affecting electrolyte balance. Thisremoves an otherwise limiting factor as to how much beta-hydroxybutyratecan be administered when administered in salt form. In addition,beta-hydroxybutyrate esters, particularly by themselves or when theprimary source of beta-hydroxybutyrate, have an unpleasant taste and arenot always well tolerated.

Beta-hydroxybutyric acid compositions can be useful as a weight losssupplement, as treatment for high blood glucose or type II diabetes, asbrain tonic, as athletic performance enhancer, as preventative againstmetabolic dysfunction, mitochondrial defect, insulin resistance, asadjunct to a ketogenic diet, as anti-aging supplement, and for otheruses associated with improved metabolic health.

Beta-hydroxybutyric acid compositions can be used in a method forincreasing ketone body level in a subject in need thereof, includingpromoting and/or sustaining ketosis in the subject, comprisingadministering to the subject a nutritionally or pharmaceuticallyeffective amount of beta-hydroxybutyric acid. Benefits of increasedketone body level in a subject include one or more of appetitesuppression, weight loss, fat loss, reduced blood glucose level,improved mental alertness, increased physical energy, improved cognitivefunction, reduction in traumatic brain injury, reduction in effect ofdiabetes, improvement of neurological disorder, reduction of cancer,reduction of inflammation, anti-aging, antiglycation, reduction inepileptic seizer, improved mood, increased strength, increased musclemass, or improved body composition.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. It is to be understood that both the foregoing brief summary andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments disclosed herein or asclaimed.

DETAILED DESCRIPTION I. Introduction

Disclosed herein are beta-hydroxybutyric acid compositions for oraldelivery and methods for their delivery, such as to increase ketone bodylevel in a subject, including to promote and/or sustain ketosis in asubject while not affecting electrolytic balance and without causingacute acidosis or gastrointestinal (GI) distress. Thebeta-hydroxybutyric acid compositions are typically administered as anaqueous composition, suspension, or gel. Powder or solidbeta-hydroxybutyric acid can be mixed with water, aqueous liquid, otherliquid, gel, or food to form a solution containing beta-hydroxybutyricacid as a solute or a suspension containing beta-hydroxybutyric acidparticles.

“Ketosis” refers to a subject having blood ketone levels within therange of about 0.5 mmol/L and about 16 mmol/L. Ketosis may improvemitochondrial function, decrease reactive oxygen species production,reduce inflammation, and increase the activity of neurotrophic factors.“Keto-adaptation” as used herein refers to prolonged nutritional ketosis(>1 week) to achieve a sustained nonpathological “mild ketosis” or“therapeutic ketosis.”

In some cases, “elevated ketone body level” may not mean that a subjectis in a state of “clinical ketosis” but nevertheless has an elevatedsupply of ketones for producing energy and/or for carrying out otherbeneficial effects of ketone bodies. For example, a subject that is“ketone adapted” may not necessarily have elevated blood serum levels ofketone bodies but rather is able to utilize available ketone bodies morerapidly compared to a subject that is not “ketone adapted.” In suchcase, “elevated ketone body level” can refer to the total quantityand/or rate of ketone bodies being utilized by the subject rather thanblood plasma levels per se.

“Exogenous ketone body” refers to beta-hydroxybutyrate and acetoacetatecompounds that are not produced by a mammal. These compounds may beutilized by a subject’s body as an energy source during instances of lowglucose levels or when these compounds are supplemented in a usableform.

“Beta-hydroxybutyric acid” refers to exogenous beta-hydroxybutyric acidthat can be in the form of a powder, other solid, solid particles in asuspension (e.g., sauce or gel), or solute in a solution, such as anaqueous solution.

“Aqueous beta-hydroxybutyric acid” refers to beta-hydroxybutyric aciddissolved in water or other aqueous liquid, in powder or other solidform, or in a gel or other suspension. Beta-hydroxybutyric acid that hasself-polymerized to form an insoluble precipitate is not “aqueousbeta-hydroxybutyric acid”, although one will appreciate that aqueousbeta-hydroxybutyric acid compositions may contain insoluble precipitateswithout causing harm.

A “suspension” means a liquid, syrup, gel, or other non-rigidcomposition with insufficient water to fully dissolve thebeta-hydroxybutyric acid, at least a portion of which remains asundissolved particles surrounded by the suspending liquid, syrup, gel,or other non-rigid composition or carrier. Non-limiting examples ofsuspending agents include gels, foods, sauces, syrups, oils, and thelike.

A “gel” refers to a composition that includes a gelling agent, such as ahydrocolloid, and a carrier, such as water or aqueous mixture. Gels canbe in the form of a thick liquid, such as a viscous Newtonian fluid, orin the form of a Bingham plastic that does not flow under the force ofgravity but can be deformed by applying pressure or other force.

Beta-hydroxybutyric acid compositions may be enriched with or containenantiomerically pure R-beta-hydroxybutyric acid, enriched with orcontain enantiomerically pure S-beta-hydroxybutyric acid, or be providedas a racemic mixture of R- and S-enantiomers. Beta-hydroxybutyric acidcompositions, specifically those containing a racemic mixture or thatare enriched with or contain enantiomerically pure,R-beta-hydroxybutyric acid, are free or substantially free ofbeta-hydroxybutyrate salts. Beta-hydroxybutyric acid compositionscontaining more S-beta-hydroxybutyric acid than R-beta-hydroxybutyricacid may be buffered with higher amounts of beta-hydroxybutyrate salt(s)when mixed with water.

Beta-hydroxybutyric acid compositions may optionally include acetoaceticacid, ester forms of beta-hydroxybutyrate and/or acetoacetate, ketonebody precursors such as 1,3-butanediol or ester thereof.

Beta-hydroxybutyrate is the deprotonated form of beta-hydroxybutyricacid having the formula CH₃CH₂OHCH₂COOH. The deprotonated form presentat typical biological pH levels is CH₃CH₂OHCH₂COO⁻. The general chemicalstructure of beta-hydroxybutyrate is:

where, X can be hydrogen, metal ion, amino cation such as from an aminoacid, alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is beta-hydroxybutyric acid. When Xis a metal ion or an amino cation, the compounds is abeta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, thecompounds is a beta-hydroxybutyrate ester. The foregoing compounds canbe in any desired physical form, such as crystalline, powder, solid,liquid, solution, suspension, or gel.

Acetoacetate is the deprotonated form of acetoacetic acid having theformula CH₃COCH₂COOH. The deprotonated form present at typicalbiological pH levels is CH₃COCH₂COO⁻. The general chemical structure ofacetoacetate is:

where, X can be hydrogen, metal ion, amino cation such as from an aminoacid, alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is acetoacetic acid. When X is ametal ion or an amino cation, the compounds is an acetoacetate salt.When X is alkyl, alkenyl, aryl, or acyl, the compounds is anacetoacetate ester. The foregoing compounds can be in any desiredphysical form, such as crystalline, powder, solid, liquid, solution,suspension, or gel.

Unless otherwise specified, the term “salt” does not mean or imply anyparticular physical state, such as a crystalline, powder, other solidform, dissolved in water to form a liquid solution, dispersed in aliquid to form a suspension, or gel. A salt can be formed in solution,such as by at least partially neutralizing beta-hydroxybutyric acid witha strong or weak base, such as an alkali or alkaline earth metalhydroxide, carbonate, or bicarbonate, basic amino acid, and the like.

As used herein, “subject” or “patient” refers to members of the animalkingdom, including mammals, such as but not limited to, humans and otherprimates; rodents, fish, reptiles, and birds. The subject may be anyanimal requiring therapy, treatment, or prophylaxis, or any animalsuspected of requiring therapy, treatment, or prophylaxis. Prophylaxismeans that regiment is undertaken to prevent a possible occurrence, suchas where a high glucose or diabetes is identified. “Patient” and“subject” are used interchangeably herein.

Beta-hydroxybutyric acid compositions can include enantiomerically pureR-beta-hydroxybutyric acid, enantiomerically pure S-beta-hydroxybutyricacid, a non-racemic mixture enriched with R-beta-hydroxybutyric acidrelative to S-beta-hydroxybutyric acid, a non-racemic mixture enrichedwith S-beta-hydroxybutyric acid relative to R-beta-hydroxybutyric acid,or a racemic mixture of R- and S-beta-hydroxybutyric acids.

Whether the beta-hydroxybutyrate free acid, salt, or ester is the R- orS-enantiomer depends on the tetrahedral orientation of the hydroxy onthe 3-carbon (beta-carbon) in relationship to the planar carboxyl group.R-beta-hydroxybutyrate is the endogenous form of beta-hydroxybutyricacid and can be utilized by a patient’s body as a fuel source duringinstances of low glucose levels in the subject or when a patient’s bodyis supplemented with a usable form of beta-hydroxybutyrate.S-beta-hydroxybutyrate is not endogenously produced by mammals but canpromote one or more of: increased endogenous production ofR-beta-hydroxybutyrate and acetoacetate; endogenous conversion into oneor both of R-beta-hydroxybutyrate and acetoacetate; endogenousconversion into fatty acids and sterols; prolonged ketosis; directmetabolism of S-beta-hydroxybutyrate; improved fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling to modulate metabolism of R-beta-hydroxybutyrate andglucose; antioxidant activity; and production of acetyl-CoA.

The term “unit dose” refers to a dosage form that is configured toorally deliver a specified quantity or dose of beta-hydroxybutyric acid.Example dosage forms of beta-hydroxybutyric acid include, but are notlimited to, drinks (such as flavored, vitamin fortified, alcoholic, ornon-alcoholic) in premeasured form, such as a can, bottle, carton, jug,and the like, drink additives, liquid energy shots, energy gel packs,foods, food additives, dietetically acceptable sprays (such as flavoredmouth spray), and premeasured quantity of powder, solid, or gel, such aspackets, pouches, tablets, capsules, effervescent tablets, and the like.Such dosage forms may be configured to provide a full unit dose orfraction thereof (e.g., ½, ⅓, or ¼ of a unit dose).

Another dosage form that can be used to provide a unit dose ofbeta-hydroxybutyric acid is a unit dose measuring device, such as a cup,scoop, syringe, dropper, spoon, spatula, or ladle, which is configuredto hold therein a measured quantity of composition equaling a full unitdose or fraction thereof (e.g., ½, ⅓, or ¼ of a unit dose). For example,a bulk container, such as a carton, box, can, jar, bag, pouch, bottle,jug, or keg, containing several unit doses of composition (e.g., 5-250or 10-150 unit doses) can be provided to a user together with a unitdose measuring device that is configured to provide a unit dose, orfraction thereof, of composition or component thereof.

A kit for use in providing beta-hydroxybutyric acid as disclosed hereinin bulk form, while providing unit doses of the composition, maycomprise a bulk container holding therein a quantity of composition anda unit dose measuring device configured to provide a unit dose, orfraction thereof, of composition or component thereof. One or more unitdose measuring devices may be positioned inside the bulk container atthe time of sale, attached to the outside of the bulk container,prepackaged with the bulk container within a larger package, or providedby the seller or manufacture for use with one or multiple bulkcontainers. A bulk container may contain liquid or solid forms ofbeta-hydroxybutyric acid.

The kit may include instructions regarding the size of the unit dose, orfraction thereof, and the manner and frequency of administration. Theinstructions may be provided on the bulk container, prepackaged with thebulk container, placed on packaging material sold with the bulkcontainer, or otherwise provided by the seller or manufacturer (e.g., onwebsites, mailers, flyers, product literature, etc.) The instructionsfor use may include a reference on how to use the unit dose measuringdevice to properly deliver a unit dose or fraction thereof. Theinstructions may additionally or altematively include a reference tocommon unit dose measuring devices, such as cups, scoops, syringes,droppers, spoons, spatulas, ladles, and the like, not provided with thebulk container (e.g., in case the provided unit dose measuring device islost or misplaced). In such case, a kit may be constructed by the enduser when following instructions provided on or with the bulk container,or otherwise provided by the seller regarding the product and how toproperly deliver a unit dose of composition, or fraction thereof.

In one embodiment, the container includes a quantity of tablets orcapsules, such as effervescent tablets, each of which includes apremeasured quantity of beta-hydroxybutyric acid as a full or fractionaldose. Capsules or tablets may further be grouped or contained withinindividual packets or pouches within the storage container, eachcontaining a plurality of tablets or capsules that provide apre-measured dosage of beta-hydroxybutyric acid.

The term “administration” or “administering” is used herein to describethe process in which the aqueous beta-hydroxybutyric acid compositionsare orally delivered to a subject.

In some embodiments, the aqueous beta-hydroxybutyric acid compositionsmay be combined with a nutritionally or pharmaceutically acceptablecarrier or additive.

II. Beta-Hydroxybutyric Acid Compositions

Administration of beta-hydroxybutyric acid in the form of an aqueoussolution, readily digestible gel or suspension, provides a source ofreadily usable ketone bodies for producing metabolic energy. This istrue regardless of whether the user is technically in state of ketosis.The body is able to metabolize both glucose and ketone bodies whenpresent. If a sufficient quantity of beta-hydroxybutyric acid isconsumed in a given time period, it can result in elevated and/orsustained blood levels of ketone bodies, thereby exploiting themetabolic and physiological advantages of ketosis without introducing asignificant quantity of electrolytes into the blood. Raising ketone bodylevel in the blood using exogenous ketones provides a subject withgreater flexibility in diet options as compared to a method that aims toinduce and sustain ketosis based on diet alone (e.g., based on fastingand/or limited carbohydrate intake). A subject that consumes anappropriate amount of beta-hydroxybutyric acid can eat an occasionalcarbohydrate or sugar-based food without jeopardizing the ketogenicstate and shifting back into a glucose-based metabolic state. Further,administration of exogenous beta-hydroxybutyric acid facilitates easiertransition to a ketogenic state while reducing or eliminatingdetrimental effects typically associated with entering ketosis.

Subjects entering or maintaining a ketogenic state may already be in astate of electrolyte imbalance due to metabolic shifts involved withketosis, including enhanced diuretic effects and changes in insulinprofiles. Thus, while there are many benefits to the administration ofbeta-hydroxybutyrate to promote or sustain ketosis in a subject, theresulting electrolyte imbalance when administering an excessive quantityand/or imbalanced ratio of salts and its associated detrimentalphysiological effects can offset the benefits of ketosis and/or make itmore difficult for a subject to maintain ketosis at the desired levelsor for a desired length of time.

For example, a formulation containing high levels and/or proportions ofsodium beta-hydroxybutyrate can sharply increase sodium level in thesubject. Excessive sodium can have detrimental effects, such ashypertension and poor cardiovascular health. High levels of sodiumrelative to potassium promotes hypertension and increases the risk ofcardiovascular disease. A formulation containing high levels and/orproportions of calcium beta-hydroxybutyrate can sharply increase calciumlevel in the subject. Excessive calcium can build up in soft tissues,leading to detrimental calcification and hardening of such tissues andraising the risk of heart disease (e.g., associated with hardenedarteries), kidney stones, arthritis, and other problematic conditions.

Aqueous beta-hydroxybutyric acid solutions, gels, and readily digestiblesuspensions provide a therapeutically effective amount ofbeta-hydroxybutyrate in the acid, and therefore most readily availableform, without contributing significant or any salts. Such compositionsprovide the advantages of promoting, initiating, and/or sustainingketosis without significantly altering electrolyte balance in the user,and in some cases even improving or easing electrolyte imbalances.

In general, aqueous beta-hydroxybutyric acid compositions for oraldelivery that are free or substantially free of beta-hydroxybutyratesalts are effective in rapidly raising blood ketone levels withoutcausing acute acidosis or gastrointestinal (GI) distress when consumedin sufficiently dilute form. In the absence of significant quantities ofbeta-hydroxybutyrate salts containing alkali or alkaline earth metalions, aqueous beta-hydroxybutyric acid solutions can deliver exogenousketone bodies without significantly altering electrolyte balance. Byproviding aqueous beta-hydroxybutyric acid at a concentration withinspecific ranges, it is possible to maintain beta-hydroxybutyric acidstability and prevent self-esterification and precipitation.

In some embodiments, aqueous beta-hydroxybutyric acid solutions can havea concentration that is sufficiently diluted such that volumes in arange of about 4 oz. (about 120 ml) to about 16 oz. (about 475 ml) candeliver a quantity of ketone bodies in a range of about 0.5 gram toabout 25 grams, without harming the stomach or causing significantacidosis. For example, dilute aqueous beta-hydroxybutyric acid solutionscan have a concentration of beta-hydroxybutyric acid in a range of about0.4% w/v to about 6% w/v, or about 0.6% w/v to about 5.5% w/v, or about0.9% w/v to about 5% w/v, or about 1.2% w/v to about 4.5% w/v, or about1.5% w/v to about 4% w/v. Although aqueous beta-hydroxybutyric acidsolutions are moderately acidic, with a pH of about 3.5 to 4, whendiluted with sufficient water, the water itself acts as a pseudobuffering agent that offsets the otherwise harsh effects of the acidwhen consumed orally.

In some embodiments, aqueous beta-hydroxybutyric acid solutions can beprovided as a concentrate for later dilution by the user, such as withwater, juice, drink, energy shot, or other aqueous composition to aconcentration in a range of about 0.4% w/v to about 6% w/v, or about0.6% w/v to about 5.5% w/v, or about 0.9% w/v to about 5% w/v, or about1.2% w/v to about 4.5% w/v, or about 1.5% w/v to about 4% w/v.Concentrated solutions may comprise beta-hydroxybutyric acid in a rangeof about 6% w/v to about 60% w/v, or about 8% w/v to about 55% w/v, orabout 10% w/v to about 50% w/v, or about 12.5% w/v to about 45% w/v, orabout 15% w/v to about 40% w/v, and then diluted by the user as desired,such as from about 2 to about 30 times, or about 3 to about 25 times, orabout 4 to about 20 times, or about 5 to about 15 times, with water,juice, drink, or other aqueous composition, as desired. Preferably, theaqueous beta-hydroxybutyric acid solutions will not be so concentratedthat they will self-polymerize and form significant amounts ofprecipitates, although it should be understood that such polymerizedprecipitates are harmless and some may be re-hydrolyzed in acidicsolutions, perhaps under certain conditions in the stomach when consumedwith sufficient water.

Beta-hydroxybutyric acid compositions are free or substantially free ofbeta-hydroxybutyrate salts so as to contain less than 1%, or less than0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or lessthan 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, orless than 0.1% of one or more beta-hydroxybutyrate salts by combinedweight of beta-hydroxybutyric acid and beta-hydroxybutyrate salt(s).Beta-hydroxybutyric acid compositions can be essentially or totally freeof beta-hydroxybutyrate salts, i.e., contain 0% by weight ofbeta-hydroxybutyrate salts.

In some embodiments, beta-hydroxybutyric acid compositions may containone or more nutritionally or pharmaceutically acceptable carriers oradditives. For example, beta-hydroxybutyric acid compositions mayoptionally include at least one additive selected from acetoacetic acid,ethanol, glycerin, propylene glycol, 1,3-butanediol, gelling agents(e.g., gellan gum, pectin, agar, carrageenan, xanthan gum, alginate,starch, modified starch, gum Arabic, guar gum, locust bean gum, konjacmaanan, gum tragacanth, acacia gum, gum karaya, methyl cellulose, agar,pullulan, konjac, hydroxypropylmethyl cellulose, other cellulosiccompounds, other polysaccharide gums, gelatin, collagen, casein, otherproteins, silica fume, milled chia seeds, and other hydrocolloids),effervescing agents (e.g., edible acid and bicarbonate or carbonatecompound), beta-hydroxybutyrate esters, vitamins, minerals, centralnervous system stimulants, nootropics, edible acids, amino acids,muscle-promoting compounds, (e.g., beta-hydroxy beta-methylbutyrate(HMB)), one or more cannabinoids (e.g., tetrahydrocannabinol and/orcannabidiol), and the like. The beta-hydroxybutyric acid composition mayinclude flavoring agents, such as essential oils, e.g., peppermint,spearmint, wintergreen, or citrus oils, natural and artificialsweeteners, and other flavorants known in the art.

Aqueous beta-hydroxybutyric acid compositions containing less than 1% ofone or more beta-hydroxybutyrate salts by combined weight ofbeta-hydroxybutyric acid and beta-hydroxybutyrate salt(s) inherentlyhave an acidic pH (i.e., pH of less than 7) because beta-hydroxybutyricacid, a weak acid, has a pKa of 4.7. Depending on the concentration ofbeta-hydroxybutyric acid in water and the amount, if any, ofbeta-hydroxybutyrate salt(s) and/or other edible acid(s), the pH ofaqueous beta-hydroxybutyric acid compositions will typically be lessthan 6.5, preferably less than about 6, or less than about 5.5, or lessthan about 5, or less than about 4.5, or less than about 4 (e.g.,between about 3.5 to 4).

In some embodiments, concentrated or dilute beta-hydroxybutyric acidsolutions, gels, sauces, and other compositions can be manufactured bycombining a powder or other solid form of beta-hydroxybutyric acid withwater, drink, beverage, sauce, gel, or other liquid or semi-liquid drinkor food product. When the beta-hydroxybutyric acid solution is preparedby a user, the powder or other solid form of beta-hydroxybutyric acidwill advantageously include a flavoring agent and may contain otheradditives, such as one or more of stabilizer (e.g., edible acids,silica, starch, and the like), effervescing agents (e.g., bicarbonate,carbonate, and optionally another acid), vitamin, mineral, stimulant,nootropic, vasodilator, cannabinoid, amino acid, and the like.

The powder, other solid, or gel may be provided in individual pre-dosedpackets, pouches, tablets, or capsules, or it may be provided in a kitwith a measuring device configured to measure out a predetermined doseor fraction thereof. A plurality (e.g., 2 or 3) of dissolvable tabletsrepresenting a single dose can be packaged together in a packet, pouch,or other container. In some embodiments, a dissolvable tablet may beeffervescent and fizz when added to water. In the case of aneffervescent tablet, it may be desirable to include a quantity of anedible acid (e.g., citric, malic, fumaric, lactic, tartaric, malonic,succinic, adipic, folic, or butyric) together with a bicarbonate salt toprovide the desired effervescent action yet provide less than 1% oftotal beta-hydroxybutyrate salt(s) upon dissolution in water (i.e., ifthe edible acid has a lower pKa than beta-hydroxybutyric acid a salt ofthe edible acid will form preferentially over beta-hydroxybutyratesalt).

In various embodiments, beta-hydroxybutyric acid compositions mayinclude enantiomerically pure R-beta-hydroxybutyric acid, a racemicmixture of R- and S-beta-hydroxybutyric acid (i.e., a mixture having a1:1 ratio of R-beta-hydroxybutyric acid and S-beta-hydroxybutyric acidenantiomers), a non-racemic mixture enriched with the R-enantiomer, or anon-racemic mixture enriched with the S-enantiomer. In some embodimentsit is advantageous to include at least some amount ofS-beta-hydroxybutyric acid in addition to or instead ofR-beta-hydroxybutyric acid.

In a first embodiment, beta-hydroxybutyric acid compositions contain anon-racemic mixture enriched with the R-enantiomer, such as greater than50% and less than 100% by enantiomeric equivalents of exogenousR-beta-hydroxybutyric acid and less than 50% and greater than 0% byenantiomeric equivalents of exogenous S-beta-hydroxybutyric acid. Insome embodiments, a non-racemic mixture of R- and S-beta-hydroxybutyricacid forms contain 50.1% to 99.9%, 50.2% to 99.8%, 50.3% to 99.7%, 50.4%to 99.6%, 50.5% to 99.5%, 51% to 99%, 52% to 98%, 53% to 97%, 54% to96%, 55% to 95%, 57% to 93%, or 60% to 90% by enantiomeric equivalentsof R-beta-hydroxybutyric acid and 49.9% to 0.1%, 49.8% to 0.2%, 49.7% to0.3%, 49.6% to 0.4%, 49.5% to 0.5%, 49% to 1%, 48% to 2%, 47% to 3%, 46%to 4%, 45% to 5%, 43% to 7%, 41% to 15%, or 40% to 10% by enantiomericequivalents of S-beta-hydroxybutyric acid.

In a second embodiment, beta-hydroxybutyric acid compositions contain anon-racemic mixture enriched with the S-enantiomer, such as greater than50% and less than 100% by enantiomeric equivalents of exogenousS-beta-hydroxybutyric acid and less than 50% and greater than 0% byenantiomeric equivalents of exogenous R-beta-hydroxybutyric acid. Insome embodiments, a non-racemic mixture of S- and R-beta-hydroxybutyricacid forms contain 50.1% to 99.9%, 50.2% to 99.8%, 50.3% to 99.7%, 50.4%to 99.6%, 50.5% to 99.5%, 51% to 99%, 52% to 98%, 53% to 97%, 54% to96%, 55% to 95%, 57% to 93%, or 60% to 90% by enantiomeric equivalentsof S-beta-hydroxybutyric acid and 49.9% to 0.1%, 49.8% to 0.2%, 49.7% to0.3%, 49.6% to 0.4%, 49.5% to 0.5%, 49% to 1%, 48% to 2%, 47% to 3%, 46%to 4%, 45% to 5%, 43% to 7%, 41% to 15%, or 40% to 10% by enantiomericequivalents of R-beta-hydroxybutyric acid.

In a third embodiment, beta-hydroxybutyric acid compositions contain aracemic (or near racemic) mixture of R-beta-hydroxybutyric acid andS-beta-hydroxybutyric acid, i.e., that contains 50% by enantiomericequivalents of exogenous R-beta-hydroxybutyric acid and 50% byenantiomeric equivalents of exogenous S-beta-hydroxybutyric acid. A nearracemic mixture that is not a perfect 50:50 mixture of RandS-enantiomers may include about 49.9% to about 50.1%, or about 49.92% toabout 50.08%, or about 49.94% to about 50.06%, or about 49.96% to about50.04%, or about 49.98% to about 50.02%, by enantiomeric equivalents ofR-beta-hydroxybutyrate and about 50.1% to about 49.9%, or about 50.06%to about 49.94%, or about 50.04% to about 49.96%, or about 50.02% toabout 49.98%, by enantiomeric equivalents of S-beta-hydroxybutyrate.

In a fourth embodiment, beta-hydroxybutyric acid compositions containenantiomerically pure S-beta-hydroxybutyric acid, i.e., that contains100% by enantiomeric equivalents of exogenous S-beta-hydroxybutyric acidand 0% by enantiomeric equivalents of R-beta-hydroxybutyric acid.

In a fifth embodiment, beta-hydroxybutyric acid compositions containenantiomerically pure R-beta-hydroxybutyric acid, i.e., that contains100% by enantiomeric equivalents of exogenous R-beta-hydroxybutyric acidand 0% by enantiomeric equivalents of S-beta-hydroxybutyric acid.Because exogenous R-beta-hydroxybutyric acid dissolved in water to forman aqueous solution with a “water buffer” is not found in nature, it isnot a “natural product”.

It is generally understood that only enantiomerically pureR-beta-hydroxybutyric acid and/or R-beta-hydroxybutyrate is producedendogenously and naturally by mammals so as to be a natural product. Atbiological pH, the endogenous form of beta-hydroxybutyric acid onlyexists as substantially deprotonated R-beta-hydroxybutyrate anions andnot in powder or other solid form, concentrated solution, or even diluteaqueous R-beta-hydroxybutyric acid within the disclosed concentrations.

S-beta-hydroxybutyric acid (S-beta-hydroxybutyrate at biological pH),which is not endogenously produced by mammals and is believed by some tobe unnatural and potentially harmful, can provide other beneficialeffects. These include one or more of: increased endogenous productionof R-beta-hydroxybutyrate and acetoacetate; endogenous conversion intoone or both of R-beta-hydroxybutyrate and acetoacetate; endogenousconversion into fatty acids and sterols; prolonged ketosis; metabolismof S-beta-hydroxybutyrate independent of its conversion toR-beta-hydroxybutyrate and/or acetoacetate; improved fetal development;increased growth years; reduced endogenous production of acetone duringketosis; signaling to modulate metabolism of R-beta-hydroxybutyrate andglucose; antioxidant activity; and production of acetyl-CoA.

Beta-hydroxybutyric acid enriched with, or that containsenantiomerically pure, S-beta-hydroxybutyric acid may be administered inhigher doses than compositions enriched with, or that containenantiomerically pure, R-beta-hydroxybutyric acid to obtain the samerapid supply of R-beta-hydroxybutyrate in the body. In such cases, itmay be desirable to include incrementally higher, but still small,amounts of beta-hydroxybutyrate salts, such as less than 4.0%, or lessthan 3.75%, or less than 3.5%, or less than 3.25%, or less than 3.0%, orless than 2.75%, or less than 2.5% or less than 2.25%, or less than 2%,or less than 1.75%, or less than 1.5%, or less than 1.25%, of such saltsby combined weight of beta-hydroxybutyric acid and beta-hydroxybutyratesalt(s), in order to further offset the greater acidity of higherconcentrations and/or amounts of beta-hydroxybutyric acid incompositions that are enriched with, or contain enantiomerically pure,S-beta-hydroxybutyric acid.

In some embodiments, beta-hydroxybutyric acid compositions mayoptionally include beta-hydroxybutyrate salts in which the cations areprovided by an amino acid or other organic compound having a netpositive charge at acidic pH. beta-hydroxybutyrate-amino acid compoundscan provide a soluble form of beta-hydroxybutyrate without providingelectrolytes such as sodium, potassium, calcium or magnesium. Most aminoacids have a net positive charge at acidic pH. Examples includearginine, lysine, leucine, iso-leucine, histidine, ornithine,citrulline, glutamine, or other suitable amino acids or metabolites ofamino acids (e.g., creatine). Some amino acids also provide healthbenefits. For example, arginine and citrulline can increase nitric oxidein the blood, which dilates blood vessels and improves blood circulationfor persons with heart conditions (and may help men suffering fromerectile dysfunction).

In some embodiments, beta-hydroxybutyric acid compositions can beprovided as an aqueous solution, such as in the form of a beverage, aconcentrated energy shot, or mouth spray for fast delivery andabsorption. Beta-hydroxybutyric acid compositions can be provided asgel, such as an energy gel. Beta-hydroxybutyric acid compositions can beprovided as a food product, such as a sauce or condiment.Beta-hydroxybutyric acid compositions can be provided as a powder orother solid that can be added to water, drink or food to form aningestible aqueous solution, gel or suspension.

In addition to water, beta-hydroxybutyric acid compositions mayoptionally include other liquid carriers, such as water, ethanol,glycerin, propylene glycol, 1,3-propandiol, and the like. Thecompositions may include vitamins and/or minerals. Other additivesinclude metabolites that enhance the effect or transport of ketonebodies into mitochondria, caffeine, theobromine, and nootropics, such asL-alpha glycerylphosphorylcholine (“alpha GPC”). The compositions mayinclude flavoring agents, such as essential oils, e.g., peppermint,spearmint, wintergreen, or citrus oils, natural and artificialsweeteners, and other flavorants known in the art.

Beta-hydroxybutyric acid compositions can optionally include one or morebeta-hydroxybutyrate esters. Example beta-hydroxybutyrate esters includemono-, di-, tri-, oligo-, and polyesters. Examples include mono-ester ofethanol, mono-ester of 1-propanol, mono-ester of 1,2-propanediol,di-ester of 1,2-propanediol, mono-ester of 1,3-propanediol, di-ester of1,3-propanediol, mono- or di-ester of S-, R-, or S-R-1,3-butanediol,mono-, di-, or tri-ester of glycerin, ester of acetoacetate, dimers,trimers, oligomers, and polyesters containing repeating units ofbeta-hydroxybutyrate, and complex oligomers or polymers ofbeta-hydroxybutyrate and one or more other hydroxy-carboxylic acids,such as lactic acid, citric acid, acetoacetic acid, quinic acid,shikimic acid, salicylic acid, tartaric acid, and malic acid, and/orbeta-hydroxybutyrate and or one or more diols, such as 1,3-propanedioland 1,3-butanediol, and one or more polyacids, such as tartaric acid,citric acid, malic acid, succinic acid, and fumaric acid.

Where it is desired to deliver essentially pure beta-hydroxybutyricacid, the beta-hydroxybutyric acid compositions will preferably containgreater than 99% by weight of beta-hydroxybutyric acid and less than 1%,less than about 0.9%, less than about 0.8%, less than about 0.7%, lessthan about 0.6%, or less than about 0.5%, by combined weight ofbeta-hydroxybutyrate salt(s), 1,3-butanediol, and ketone esters (i.e.,beta-hydroxybutyrate and/or acetoacetate esters) by total combinedweight of the beta-hydroxybutyric acid and any of beta-hydroxybutyratesalt(s), 1,3-butanediol, or ketone ester that may be present, exclusiveof water and other components unrelated to ketone bodies. Stated anotherway, beta-hydroxybutyric acid compositions can have a weight ratio ofbeta-hydroxybutyric acid to combined beta-hydroxybutyrate salt(s),1,3-butanediol, and ketone esters or greater than 99:1, greater thanabout 99.1:0.9, greater than about 99.2:0.8, greater than about99.3:0.7, greater than about 99.4:0.6, or greater than about 99.5:0.5.

Beta-hydroxybutyric acid compositions may optionally include short-,medium, and/or long-chain fatty acids and/or esters thereof. Most ofsuch components can have limited solubility in water and may require useof emulsifier and/or remain as particles in suspension, while watersoluble forms, particularly short chain fatty acids, have a very strongtaste. Short chain fatty acids contain 2 to 5 carbon atoms and includeacetic acid, propionic acid, butyric acid, isobutyric acid, valericacid, and isovaleric acid. Medium chain fatty acids contain from 6 to 12carbons and include caproic acid, caprylic acid, capric acid, and lauricacid. Long chain fatty acids contain more than 12 carbon atoms andinclude myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, cerotic acid, omega-3 fatty acids,omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids. Inpreferred embodiments, aqueous beta-hydroxybutyric acid compositions aresubstantially free of short-, medium-, and long-chain fatty acids andesters thereof, such as less than 5%, 4%, 3%, 2%, or 1%.

III. Administration

Beta-hydroxybutyric acid compositions can be used in a method forincreasing ketone body level, including promoting and/or sustainingketosis, in a subject comprising administering to a subject in needthereof a nutritionally or pharmaceutically effective amount ofbeta-hydroxybutyric acid. Examples of beneficial effects of increasingketone body level, including promoting and/or sustaining ketosis, in asubject include one or more of appetite suppression, weight loss, fatloss, reduced blood glucose level, improved mental alertness, increasedphysical energy, improved cognitive function, reduction in traumaticbrain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.

Beta-hydroxybutyric acid can be administered to a subject intherapeutically effective dosages and/or in frequencies to induce orsustain ketosis. In some embodiments, a single dose may provide fromabout 0.5 gram to about 25 grams, or about 0.75 gram to about 20 grams,or about 1 gram to about 15 grams, or about 1.5 grams to about 12 grams,or about 2 grams to about 10 grams of combined weight ofbeta-hydroxybutyric acid and beta-hydroxybutyrate compounds.

Beta-hydroxybutyric acid compositions can include or be administeredtogether with other supplements, such as vitamin D₃, vitamins, minerals,nootropics, and others known in the art. Examples of vitamins, mineralsand herbal supplements that can be added to the ketogenic compositionsinclude one or more of vitamin A, vitamin C, vitamin E, niacin, vitaminB6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese,chromium, caffeine, theobromine, theacrine, methylliberine, huperzine A,epicatechins, and enzymes.

In some embodiments, the subject may follow a ketogenic diet thatrestricts intake of carbohydrates and protein during the period ofadministration. In one example embodiment, the subject may restrict thedietary intake to a ratio of about 65% fat, about 25% protein, and about10% carbohydrates. The resulting therapeutic ketosis provides a rapidand sustained keto-adaptation as a metabolic therapy for a wide range ofmetabolic disorders, and provides nutritional support for therapeuticfasting, weight loss, and performance enhancement. As such, thecomposition is typically administered once per day, twice per day, orthree times per day to a subject desiring to promote and/or sustain astate of ketosis.

In some embodiments, multiple doses of the composition are administeredover time. The frequency of administration of the composition can varydepending on any of a variety of factors, such as timing of treatmentfrom previous treatments, objectives of the treatment, and the like. Theduration of administration of the composition (e.g., the time periodover which the agent is administered), can vary depending on any of avariety of factors, including subject response, desired effect oftreatment, etc.

The amount of the composition to be administered can vary according tofactors such as the degree of susceptibility of the individual, the age,sex, and weight of the individual, idiosyncratic responses of theindividual, and the like. The “therapeutically effective amount” is thatamount necessary to promote a therapeutically effective result in vivo(i.e., therapeutic ketosis). In accordance with the present disclosure,a suitable single dose size is a dose that is capable of preventing oralleviating (reducing or eliminating) a symptom in a patient whenadministered one or more times over a suitable time period.

The amount of composition administered will depend on potency,absorption, distribution, metabolism, and excretion rates of unusedketone bodies, electrolytes, the method of administration, and theparticular disorder being treated, as well as other factors known tothose of skill in the art. The dose should be sufficient to affect adesirable response, such as a therapeutic or prophylactic responseagainst a particular disorder or condition, taking into account theseverity of the condition to be alleviated. The aqueousbeta-hydroxybutyric acid solution may be administered once, or may bedivided and administered over intervals of time. It is to be understoodthat administration may be adjusted according to individual need andprofessional judgment of a person administrating or supervising theadministration of the compositions.

Aqueous beta-hydroxybutyric acid solutions can be administered to asubject at a concentration that is sufficiently dilute such that volumesin a range of about 4 oz. (about 120 ml) to about 16 oz. (about 475 ml)can deliver a quantity of ketone bodies in a range of about 0.5 gram toabout 25 grams, without harming the stomach or causing significantacidosis. For example, dilute aqueous beta-hydroxybutyric acid solutionscan have a concentration of beta-hydroxybutyric acid in a range of about0.4% w/v to about 6% w/v, or about 0.6% w/v to about 5.5% w/v, or about0.9% w/v to about 5% w/v, or about 1.2% w/v to about 4.5% w/v, or about1.5% w/v to about 4% w/v. Although aqueous beta-hydroxybutyric acidsolutions are moderately acidic, with a pH of about 3.5 to 4, whendiluted with sufficient water, the water itself acts as a pseudobuffering agent that offsets the otherwise harsh effects of the acidwhen consumed orally.

Alternatively, aqueous beta-hydroxybutyric acid solutions can beprovided as a concentrate for later dilution by a user, such as withwater, juice, drink, energy shot, or other aqueous composition to aconcentration in a range of about 0.4% w/v to about 6% w/v, or about0.6% w/v to about 5.5% w/v, or about 0.9% w/v to about 5% w/v, or about1.2% w/v to about 4.5% w/v, or about 1.5% w/v to about 4% w/v.Concentrated solutions may comprise beta-hydroxybutyric acid in a rangeof about 6% w/v to about 60% w/v, or about 8% w/v to about 55% w/v, orabout 10% w/v to about 50% w/v, or about 12.5% w/v to about 45% w/v, orabout 15% w/v to about 40% w/v, and then diluted by the user as desired,such as from about 2 to about 30 times, or about 3 to about 25 times, orabout 4 to about 20 times, or about 5 to about 15 times, with water,juice, drink, or other aqueous composition, as desired. Preferably, theaqueous beta-hydroxybutyric acid solutions will not be so concentratedthat they will self-polymerize and form significant amounts ofprecipitates, although it should be understood that such polymerizedprecipitates are harmless and some may be re-hydrolyzed in acidicsolutions, perhaps under certain conditions in the stomach when consumedwith sufficient water.

Concentrated or dilute beta-hydroxybutyric acid solutions can bemanufactured by combining a powder or other solid form ofbeta-hydroxybutyric acid with water, drink, beverage, sauce, gel, orother liquid or semi-liquid drink, energy product, or food product. Whenthe beta-hydroxybutyric acid solution, drink, sauce, or gel is preparedby a user, the powder or other solid form of beta-hydroxybutyric acidcan be flavored and may contain other additives, such as one or more ofstabilizer, vitamin, mineral, stimulant, nootropic, vasodilator,cannabinoid, amino acid, and the like. The powder may be provided inindividual pre-dosed packets, pouches, tablets, or capsules, or it maybe provided in a kit with a measuring device configured to measure out apredetermined dose or fraction thereof. A plurality (e.g., 2 or 3) ofdissolvable tablets representing a single dose can be packaged togetherin a packet, pouch, or other container. In some embodiments, adissolvable tablet may be effervescent and fizz when added to water. Inthe case of an effervescent tablet, it may be desirable to include aquantity of an edible acid (e.g., citric or malic) together with abicarbonate or carbonate salt to provide the desired effervescent actionyet provide less than 1% of total beta-hydroxybutyrate salt(s) upondissolution in water (i.e., if the edible acid has a lower pKa thanbeta-hydroxybutyric acid a salt of the edible acid will formpreferentially over beta-hydroxybutyrate salt).

IV. EXAMPLES

The following is a description of exemplary aqueous beta-hydroxybutyricacid solutions, gels, and suspensions, and solid compositions used tomake such solutions, gels, or suspensions, useful for delivering ketonebodies to a subject in need thereof, including to induce and/or sustaina ketogenic state in a subject to which they are administered, withoutdelivering a significant quantity of electrolytes.

Example 1

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form) with waterto form a highly concentrated solution containing 60% w/v ofbeta-hydroxybutyric acid. The concentrated aqueous beta-hydroxybutyricacid solution is readily administered as a ketogenic composition toexogenously raise blood ketone level by mixing with 10 to 30 parts ofwater, juice, beverage, or other aqueous composition. The aqueousbeta-hydroxybutyric acid solution contains less than 1% by combinedweight of beta-hydroxybutyrate salt(s), 1,3-butanediol, and ketoneester, exclusive of the water.

Example 2

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form) with waterto form a highly concentrated solution containing 50% w/v ofbeta-hydroxybutyric acid. The concentrated aqueous beta-hydroxybutyricacid solution is readily administered as a ketogenic composition toexogenously raise blood ketone level by mixing with 9 to 28 parts ofwater, juice, beverage, or other aqueous composition. The aqueousbeta-hydroxybutyric acid solution contains less than 1% by combinedweight of beta-hydroxybutyrate salt(s), 1,3-butanediol, and ketoneester, exclusive of the water.

Example 3

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a less highly concentratedsolution containing 40% w/v of beta-hydroxybutyric acid. Theconcentrated aqueous beta-hydroxybutyric acid solution is readilyadministered as a ketogenic composition to exogenously raise bloodketone level by mixing with 8 to 25 parts of water, juice, beverage, orother aqueous composition. The aqueous beta-hydroxybutyric acid solutioncontains less than 1% by combined weight of beta-hydroxybutyratesalt(s), 1,3-butanediol, and ketone ester, exclusive of the water.

Example 4

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a less highly concentratedsolution containing 35% w/v of beta-hydroxybutyric acid. Theconcentrated aqueous beta-hydroxybutyric acid solution is readilyadministered as a ketogenic composition to exogenously raise bloodketone level by mixing with 7 to 22 parts of water, juice, beverage, orother aqueous composition. The aqueous beta-hydroxybutyric acid solutioncontains less than 1% by combined weight of beta-hydroxybutyratesalt(s), 1,3-butanediol, and ketone ester, exclusive of the water.

Example 5

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a moderately concentratedsolution containing 30% w/v of beta-hydroxybutyric acid. Theconcentrated aqueous beta-hydroxybutyric acid solution is readilyadministered as a ketogenic composition to exogenously raise bloodketone level by mixing with 6 to 18 parts of water, juice, beverage, orother aqueous composition. The aqueous beta-hydroxybutyric acid solutioncontains less than 1% by combined weight of beta-hydroxybutyratesalt(s), 1,3-butanediol, and ketone ester, exclusive of the water.

Example 6

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a moderately concentratedsolution containing 25% w/v of beta-hydroxybutyric acid. Theconcentrated aqueous beta-hydroxybutyric acid solution is readilyadministered as a ketogenic composition to exogenously raise bloodketone level by mixing with 5 to 15 parts of water, juice, beverage, orother aqueous composition. The aqueous beta-hydroxybutyric acid solutioncontains less than 1% by combined weight of beta-hydroxybutyratesalt(s), 1,3-butanediol, and ketone ester, exclusive of the water.

Example 7

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a moderately concentratedsolution containing 20% w/v of beta-hydroxybutyric acid. Theconcentrated aqueous beta-hydroxybutyric acid solution is readilyadministered as a ketogenic composition to exogenously raise bloodketone level by mixing with 4 to 12 parts of water, juice, beverage, orother aqueous composition. The aqueous beta-hydroxybutyric acid solutioncontains less than 1% by combined weight of beta-hydroxybutyratesalt(s), 1,3-butanediol, and ketone ester, exclusive of the water.

Example 8

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a fairly concentrated solutioncontaining 15% w/v of beta-hydroxybutyric acid. The concentrated aqueousbeta-hydroxybutyric acid solution is readily administered as a ketogeniccomposition to exogenously raise blood ketone level by mixing with 3 to9 parts of water, juice, beverage, or other aqueous composition. Theaqueous beta-hydroxybutyric acid solution contains less than 1% bycombined weight of beta-hydroxybutyrate salt(s), 1,3-butanediol, andketone ester, exclusive of the water.

Example 9

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a fairly concentrated solutioncontaining 10% w/v of beta-hydroxybutyric acid. The concentrated aqueousbeta-hydroxybutyric acid solution is readily administered as a ketogeniccomposition to exogenously raise blood ketone level by mixing with 2 to8 parts of water, juice, beverage, or other aqueous composition. Theaqueous beta-hydroxybutyric acid solution contains less than 1% bycombined weight of beta-hydroxybutyrate salt(s), 1,3-butanediol, andketone ester, exclusive of the water.

Example 10

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a fairly dilute solutioncontaining 6% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 11

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a fairly dilute solutioncontaining 5% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 12

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a moderately dilute solutioncontaining 4% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 13

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a more dilute solutioncontaining 3% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 14

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form an even more dilute solutioncontaining 2% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 15

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a very dilute solutioncontaining 1.5% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 16

An aqueous beta-hydroxybutyric acid solution is prepared by mixingbeta-hydroxybutyric acid (e.g., powder or other solid form or moreconcentrated solution) with water to form a highly dilute solutioncontaining 1% w/v of beta-hydroxybutyric acid. The aqueousbeta-hydroxybutyric acid solution can be used as is or mixed withanother substance. The composition is used to deliver ketone bodies andexogenously raise blood ketone level in a subject.

Example 17

Any of the foregoing aqueous beta-hydroxybutyric acid solutions ismodified by including a gelling agent to form a gel. The gelling agentcan be one or more of gellan gum, pectin, agar, carrageenan, xanthangum, alginate, starch, modified starch, gum Arabic, guar gum, locustbean gum, konjac maanan, gum tragacanth, acacia gum, gum karaya, methylcellulose, agar, pullulan, konjac, hydroxypropylmethyl cellulose, othercellulosic compounds, other polysaccharide gums, gelatin, collagen,casein, other proteins, silica fume, milled chia seeds, and otherhydrocolloids. The gelling agent is included in an amount to yield a gelof desired consistency, such as a viscous Newtonian fluid or a Binghamplastic. The gel composition improves taste and enhances compliance andis used to deliver ketone bodies and exogenously raise blood ketonelevel in a subject.

Example 18

Any of the foregoing beta-hydroxybutyric acid solutions or gels includeother carrier materials in which beta-hydroxybutyric acid is insolubleor less soluble in order to form a suspension containing particles ofbeta-hydroxybutyric acid. In some cases the quantity of water is reducedto be less than the amount required to dissolve the beta-hydroxybutyricacid. The suspension can be a liquid, a gel, a sauce, or other food ordrink material.

Example 19

Any of the foregoing beta-hydroxybutyric acid compositions is combinedwith one or more short chain fatty acids or ester thereof.

Example 20

Any of the foregoing beta-hydroxybutyric acid compositions is combinedwith a beta-hydroxybutyrate compound containing a cationic amino acidselected from arginine, lysine, leucine, iso-leucine, histidine,ornithine, citrulline, L-glutamine, or metabolite of an amino acid, suchas creatine). The beta-hydroxybutyrate amino acid compound provides anadditional source of beta-hydroxybutyrate without adding electrolytes tothe composition.

Example 21

Any of the foregoing beta-hydroxybutyric acid compositions can include anon-racemic mixture enriched with R-beta-hydroxybutyric acid, which canbe prepared by mixing R-beta-hydroxybutyric acid with a racemic mixtureof R- and S-beta-hydroxybutyric acids to provide greater than 50% andless than 100% by enantiomeric equivalents of R-beta-hydroxybutyric acidand less than 50% and greater than 0% by enantiomeric equivalents ofS-beta-hydroxybutyric acid. Because the non-racemic mixture includesmore of the R-enantiomer, the onset of ketosis is accelerated for agiven dosage as compared to the same dosage of a racemic mixture. On theother hand, including the S-enantiomer provides for a longer state ofketosis and/or other benefits as disclosed herein compared to using pureR-beta-hydroxybutyric acid.

Example 22

Any of the foregoing beta-hydroxybutyric acid compositions can include anon-racemic mixture enriched with S-beta-hydroxybutyric acid, which canbe prepared by mixing S-beta-hydroxybutyric acid with a racemic mixtureof R- and S-beta-hydroxybutyric acids to provide greater than 50% andless than 100% by enantiomeric equivalents of S-beta-hydroxybutyric acidand less than 50% and greater than 0% by enantiomeric equivalents ofR-beta-hydroxybutyric acid. Because the non-racemic mixture includesmore of the S-enantiomer, the onset of ketosis is delayed for a givendosage as compared to the same dosage of a racemic mixture.

Example 23

Any of the foregoing beta-hydroxybutyric acid compositions can include aracemic mixture of R-beta-hydroxybutyric acid and S-beta-hydroxybutyricacid to provide 50% by enantiomeric equivalents of the R-enantiomer and50% by enantiomeric equivalents of the S-enantiomer. Because thecomposition contains a racemic mixture, the onset of ketosis isaccelerated for a given dosage as compared to the same dosage enrichedwith the S-enantiomer. On the other hand, because the racemic mixtureincludes 50% by enantiomeric equivalents of the S-enantiomer, theduration of sustained ketosis is increased for a given dosage ascompared to the same dosage enriched with the R-enantiomer.

Example 24

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including one or more supplements, such as one or more vitamins,minerals, herbs, and others known in the art.

Example 25

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including one or more beta-hydroxybutyrate esters.

Example 26

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including one or more acetoacetate esters.

Example 27

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including 1,3-butanediol, such as R,S-1,3-butanediol,R-1,3-butanediol, S-1,3-butanediol, 1,3-butanediol enriched withR-1,3-butanediol, or 1,3-butanediol enriched with S-1,3-butanediol.

Example 28

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including one or more fat burner supplements such as green tea, greentea extract (e.g., a composition including one or more isolated greentea catechins such as epigallocatechin gallate (EGCG)), green coffeeextract, conjugated linoleic acid (CLA), tetradecyl thioacetic acid(TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine,capsaicin, raspberry ketones (e.g., 4-(4-hydroxyphenyl)butan-2-one,p-hydroxybenzyl acetone), ephedrine, synephrine (e.g.,bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine,fucoxanthin, acetylcholine modulators and/or adenosine receptorantagonists (e.g., caffeine), nicotine, coca leaf derivative, ursolicacid, clenbuterol, noradrenaline reuptake inhibitors (e.g., hordenine,atomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-keto DHEA), thyroidhormones (e.g., triiodothyronine), and combinations thereof. Theresulting combined supplement is expected to provide greater lipolysisand/or fat oxidation effects than a similar dose that includes onlybeta-hydroxybutyrate compounds.

Example 29

Any of the foregoing beta-hydroxybutyric acid compositions is modifiedby including one or more nootropic supplements such as tyrosine, L-DOPA(i.e., L-3,4-dihydroxyphenylalanine), tryptophan, and5-hydroxytryptophan (5-HTP), racetams such as such as piracetam,oxiracetam, and aniracetam, L-theanine, D-serine, phosphatidylserine,tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors suchas hordenine and atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiolarosea, Polygala tenuifolia, Muira puama, Eschscholzia californica,Convolvulus pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopamonnieri, Epimedium herbs, Ashwagandha herbs, cyclic adenosinemonophosphate (cAMP) modulators such as forskolin, stimulants such asnicotine, caffeine, and amphetamines, cholinergic compounds and/oracetylcholine modulators such as huperzine-A, dimethylaminoethanol,choline, and alpha-glycerophosphocholine, and combinations thereof. Theresulting combined supplement is expected to provide greater cognition,alertness, and/or mood effects than a similar dose that includes onlybeta-hydroxybutyrate compounds.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. A method for exogenously increasing ketone body level in a subject,comprising: administering to the subject an aqueous beta-hydroxybutyricacid composition comprised of: water; and about 0.4% w/v to about 60%w/v of exogenous beta-hydroxybutyric acid at least partially dissolvedin the water, wherein the aqueous beta-hydroxybutyric acid compositionis free or substantially free of beta-hydroxybutyrate salts so as tocontain less than 1% of total beta-hydroxybutyrate salts and greaterthan 99% of the exogenous beta-hydroxybutyric acid by combined weight ofthe beta-hydroxybutyric acid and any beta-hydroxybutyrate salts, whereinthe aqueous beta-hydroxybutyric acid composition is optionally free of1,3-butanediol and ketone esters, wherein the aqueousbeta-hydroxybutyric acid composition provides a unit dose of about 0.5gram to about 25 grams of the exogenous beta-hydroxybutyric acid inorder to exogenously increase blood ketone level in the subject.
 2. Themethod of claim 1, wherein the aqueous beta-hydroxybutyric acidcomposition is a dilute composition containing about 0.4% w/v to about6% w/v of the exogenous beta-hydroxybutyric acid.
 3. The method of claim2, wherein the method comprises: providing a concentratedbeta-hydroxybutyric acid composition containing about 6% w/v to about60% w/v of the exogenous beta-hydroxybutyric acid; diluting theconcentrated beta-hydroxybutyric acid composition with water, juice,drink, or other aqueous composition to form the dilute composition; andadministering to the dilute composition to the subject.
 4. The method ofclaim 3, wherein the concentrated beta-hydroxybutyric acid compositioncontains about 8% w/v to about 55% w/v, or about 10% w/v to about 50%w/v, or about 12.5% w/v to about 45% w/v, or about 15% w/v to about 40%w/v of the exogenous beta-hydroxybutyric acid.
 5. The method of claim 3,wherein the dilute composition contains about 0.6% w/v to about 5.5%w/v, or about 0.9% w/v to about 5% w/v, or about 1.2% w/v to about 4.5%w/v, or about 1.5% w/v to about 4% w/v of the exogenousbeta-hydroxybutyric acid.
 6. The method of claim 1, wherein about 4 oz.(about 120 ml) to about 16 oz. (about 475 ml) of the compositionprovides the unit dose of about 0.5 gram to about 25 grams of theexogenous beta-hydroxybutyric acid to the subject.
 7. The method ofclaim 7, wherein about 4 oz. (about 120 ml) to about 16 oz. (about 475ml) of the composition provides a unit dose of about 0.75 gram to about20 grams, or about 1 gram to about 15 grams, or about 1.5 grams to about12 grams, or about 2 grams to about 10 grams 0.5 gram to about 25 gramsof the exogenous beta-hydroxybutyric acid to the subject.
 8. The methodof claim 1, wherein the aqueous beta-hydroxybutyric acid compositioncontains less than about 0.9%, or less than about 0.8%, or less thanabout 0.7%, or less than about 0.6%, or less than about 0.5%, or lessthan about 0.4%, or less than about 0.3%, or less than about 0.2%, orless than about 0.1% of total beta-hydroxybutyrate salts by combinedweight of the exogenous beta-hydroxybutyric acid and anybeta-hydroxybutyrate salts.
 9. The method of claim 1, wherein theexogenous beta-hydroxybutyric acid is enantiomerically pureR-beta-hydroxybutyric acid or a non-racemic mixture enriched withR-beta-hydroxybutyric acid that contains greater than 50% and less than100% by enantiomeric equivalents of R-beta-hydroxybutyric acid and lessthan 50% and greater than 0% by enantiomeric equivalents ofS-beta-hydroxybutyric acid.
 10. The method of claim 1, wherein theexogenous beta-hydroxybutyric acid is enantiomerically pureS-beta-hydroxybutyric acid or a non-racemic mixture enriched withS-beta-hydroxybutyric acid that contains greater than 50% and less than100% by enantiomeric equivalents of S-beta-hydroxybutyric acid and lessthan 50% and greater than 0% by enantiomeric equivalents ofR-beta-hydroxybutyric acid.
 11. The method of claim 1, wherein theexogenous beta-hydroxybutyric acid is a racemic mixture ofR-beta-hydroxybutyric acid and S-beta-hydroxybutyric acid.
 12. Themethod of claim 1, wherein the method comprises: providing exogenousbeta-hydroxybutyric acid in solid or powder form; adding the exogenousbeta-hydroxybutyric acid in solid or powder to water, juice, drink, orother aqueous composition to form the aqueous beta-hydroxybutyric acidcomposition.
 13. The method of claim 1, further comprising at least oneadditive selected from the group consisting of gelling agents, flavoringagents, vitamins, minerals, central nervous system stimulants, edibleacids, amino acids, muscle-promoting compounds, and cannabinoids. 14.The method of claim 13, wherein the composition is a gel and comprisesat least one gelling agent selected from the group consisting of gellangum, pectin, agar, carrageenan, xanthan gum, alginate, starch, modifiedstarch, gum Arabic, guar gum, locust bean gum, konjac, gum tragacanth,acacia gum, gum karaya, methyl cellulose, agar, pullulan, konjac,hydroxypropylmethyl cellulose, other cellulosic compounds, otherpolysaccharide gums, gelatin, collagen, casein, other proteins, silicafume, and milled chia seeds.
 15. The method of claim 1, wherein theaqueous beta-hydroxybutyric acid composition contains greater than 99%by weight of the exogenous beta-hydroxybutyric acid and less than 1% bycombined weight of beta-hydroxybutyrate salts, 1,3-butanediol, andketone esters by total combined weight of the exogenousbeta-hydroxybutyric acid and any beta-hydroxybutyrate salts,1,3-butanediol, or ketone ester that may be present.
 16. The method ofclaim 1, wherein exogenously increasing ketone body level in the subjectresults in one or more of appetite suppression, weight loss, fat loss,reduced blood glucose level, improved mental alertness, increasedphysical energy, improved cognitive function, reduction in traumaticbrain injury, reduction in effect of diabetes, improvement ofneurological disorder, reduction of cancer, reduction of inflammation,anti-aging, antiglycation, reduction in epileptic seizer, improved mood,increased strength, increased muscle mass, or improved body composition.17. A method for exogenously increasing ketone body level in a subject,comprising: providing a concentrated beta-hydroxybutyric acidcomposition containing about 6% w/v to about 60% w/v ofbeta-hydroxybutyric acid; diluting the concentrated beta-hydroxybutyricacid composition with water, juice, drink, or other aqueous compositionto form a dilute beta-hydroxybutyric acid composition containing about0.4% w/v to about 6% w/v of the exogenous beta-hydroxybutyric acid; andadministering to the dilute beta-hydroxybutyric acid composition to thesubject, wherein the dilute beta-hydroxybutyric acid composition is freeor substantially free of beta-hydroxybutyrate salts so as to containless than 1% of total beta-hydroxybutyrate salts and greater than 99% ofthe exogenous beta-hydroxybutyric acid by combined weight of thebeta-hydroxybutyric acid and any beta-hydroxybutyrate salts, wherein thedilute beta-hydroxybutyric acid composition is optionally free of1,3-butanediol and ketone esters, wherein the dilute beta-hydroxybutyricacid composition provides a unit dose of about 0.5 gram to about 25grams of the exogenous beta-hydroxybutyric acid in order to exogenouslyincrease blood ketone level in the subject.
 18. The method of claim 17,wherein the dilute beta-hydroxybutyric acid composition contains greaterthan 99% by weight of beta-hydroxybutyric acid and less than 1% bycombined weight of beta-hydroxybutyrate salts, 1,3-butanediol, andketone esters by total combined weight of the beta-hydroxybutyric acidand any beta-hydroxybutyrate salts, 1,3-butanediol, or ketone ester thatmay be present.
 19. The method of claim 16, the dilutebeta-hydroxybutyric acid composition further comprising at least oneadditive selected from the group consisting of gelling agents, flavoringagents, vitamins, minerals, central nervous system stimulants, edibleacids, amino acids, muscle-promoting compounds, cannabinoids,acetoacetic acid, acetoacetate, 1,3-butanediol, and beta-hydroxybutyrateesters.
 20. A method for exogenously increasing ketone body level in asubject, comprising: providing exogenous beta-hydroxybutyric acid insolid or powder form; adding the exogenous beta-hydroxybutyric acid insolid or powder to water, juice, drink, or other aqueous composition toform an aqueous beta-hydroxybutyric acid composition containing about0.4% w/v to about 60% w/v of the exogenous beta-hydroxybutyric acid; andadministering to the beta-hydroxybutyric acid composition to thesubject, wherein the beta-hydroxybutyric acid composition is free orsubstantially free of beta-hydroxybutyrate salts so as to contain lessthan 1% of total beta-hydroxybutyrate salts and greater than 99% of theexogenous beta-hydroxybutyric acid by combined weight of thebeta-hydroxybutyric acid and any beta-hydroxybutyrate salts, wherein thebeta-hydroxybutyric acid composition is optionally free of1,3-butanediol and ketone esters, wherein the beta-hydroxybutyric acidcomposition provides a unit dose of about 0.5 gram to about 25 grams ofthe exogenous beta-hydroxybutyric acid in order to exogenously increaseblood ketone level in the subject.